The invention relates to substituted anthranylalkyl and -cycloalkyl amides and their use as medicaments in the treatment of diseases caused by persistent angiogenesis.
Persistent angiogenesis may be the cause of various diseases such as psoriasis, arthritis, such as rheumatoid arthritis, haemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplantation rejections and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferation diseases, artheriosclerosis and injuries to nerve tissue, or may lead to a worsening of these diseases.
The direct or indirect inhibition of the VEGF receptor can be used to treat such diseases and other VEGF-induced pathological angiogenesis and vascular permeable conditions, such as tumour vascularisation. For example, it is known that the growth of tumours can be inhibited by soluble receptors and antibodies to VEGF.
Persistent angiogenesis is induced by the VEGF through its receptor. So that VEGF can display this activity, it is necessary for VEGF to bind to the receptor and for tyrosine phosphorylation to develop.
It has now been found that compounds of general formula I: 
in which
A is the group xe2x95x90NR7,
W is oxygen, sulfur, two hydrogen atoms or the group xe2x95x90NR8,
Z is a bond or the group xe2x95x90NR10 or xe2x95x90Nxe2x80x94,
R1 is branched or unbranched C1-12-alkyl or C2-12-alkenyl which is optionally substituted once or many times by halogen, hydroxy, C1-6-alkyloxy, aralkyloxy, C1-6-alkyl and/or NR11R12; or C3-10-cycloalkyl, or C3-10-cycloalkenyl which is optionally substituted once or many times by halogen, hydroxy, C1-6-alkyloxy, aralkyloxy, C1-6-alkyl and/or NR11R12,
X is C1-6-alkyl;
R2 signifies monocyclic or bicyclic heteroaryl, which is unsubstituted or optionally substituted once or many times by halogen, C1-6-alkyl, C1-6-alkoxy and/or hydroxy,
R3, R4, R5 and R6 are hydrogen, halogen; or C1-6-alkoxy, C1-6-alkyl, C1-6-carboxyalkyl either unsubstituted or optionally substituted once or many times by halogen,
R7 is hydrogen, C1-6-alkyl or C1-8-cycloalkyl,
R8, R9 and R10 are hydrogen or C1-6-alkyl and
R11 and R12 are hydrogen or C1-6-alkyl or form a ring which may contain a further hetero atom and may be optionally substituted by C1-6-alkyl,
as well as the isomers and salts thereof, stop tyrosine phosphorylation or persistent angiogenesis and thus prevent the growth and spread of tumours.
By alkyl is understood in each case a straight-chain or branched alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert.-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl.
By cycloalkyl is understood monocyclic alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl oder cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, and also bicyclic rings or tricyclic rings, for example adamantanyl.
By cycloalkenyl is understood in each case cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, whereby linking may take place at the double bond and also at the single bonds.
Halogen is understood to be in each case fluorine, chlorine, bromine or iodine.
The alkenyl substituents are respectively straight-chained or branched and contain 2-6, preferably 2-4 carbon atoms. The following radicals may be mentioned by way of example: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, allyl.
The aryl radical respectively has 6-12 carbon atoms, for example naphthyl, biphenyl and in particular phenyl.
The heteroaryl radical may be respectively benzocondensed. Examples of 5-ring heteroaromatics are: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives, and examples of 6-ring heteroaromatics are pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo derivatives.
The aryl and the heteroaryl radical may respectively be substituted once, twice or three times by identical or different substituents from hydroxy, halogen, C1-4-alkoxy.
If an acidic function is contained therein, suitable salts are the physiologically acceptable salts of organic and inorganic bases, for example the readily soluble alkali and alkaline earth salts, as well as N-methyl-glucamine, dimethyl glucamine, ethyl glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tri-hydroxy-methyl-amino-methane, amino-propanediol, Sovak base, 1-amino-2,3,4-butanetriol.
If a basic function is contained therein, suitable salts are the physiologically acceptable salts of organic and inorganic acids, such as hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, etc.
Of particular interest are those compounds of the general formula I, in which
A is the group xe2x95x90NR7,
W is oxygen,
Z is a bond,
R1 is branched or unbranched C1-12-alkyl or C2-12-alkenyl which is optionally substituted once or many times by halogen, hydroxy, C1-6-alkyloxy, aralkyloxy, C1-6-alkyl and/or NR11R12; or C3-10-cycloalkyl, or C3-10-cycloalkenyl which is optionally substituted once or many times by halogen, hydroxy, C1-6-alkyloxy, aralkyloxy, C1-6-alkyl and/or NR11R12,
X is C1-6-alkyl;
R2 signifies monocyclic or bicyclic heteroaryl, which is unsubstituted or optionally substituted once or many times by halogen, C1-6-alkyl, C1-6-alkoxy and/or hydroxy,
R3, R4, R5 and R6 are hydrogen, halogen; or C1-6-alkoxy, C1-6-alkyl, C1-6-carboxyalkyl either unsubstituted or optionally substituted once or many times by halogen,
R7 is hydrogen, C1-6-alkyl or C1-8-cycloalkyl,
R9 is hydrogen or C1-6-alkyl and
R11 and R12 are hydrogen or C1-6-alkyl or form a ring which may contain a further hetero atom and may be optionally substituted by C16-alkyl,
as well as the isomers and salts thereof.
Of particular interest are those compounds of the general formula I, in which
A is the group xe2x95x90NR7,
W is oxygen,
Z is a bond,
R1 is branched or unbranched C1-12-alkyl or C2-12-alkenyl which is optionally substituted once or many times by halogen, hydroxy, C1-6-alkyloxy, aralkyloxy, C1-6-alkyl and/or NR11R12; or C3-10-cycloalkyl, or C3-10-cycloalkenyl which is optionally substituted once or many times by halogen, hydroxy, C1-6-alkyloxy, aralkyloxy, C1-6-alkyl and/or NR11R12,
X is C1-6-alkyl;
R2 is pyridyl,
R3, R4, R5 and R6 are hydrogen, halogen; or C1-6-alkoxy, C1-6-alkyl, C1-6-carboxyalkyl either unsubstituted or optionally substituted once or many times by halogen,
R7 is hydrogen, C1-6-alkyl or C1-8-cycloalkyl,
R9 is hydrogen or C1-6-alkyl and
R11 and R12 are hydrogen or C1-6-alkyl or form a ring which may contain a further hetero atom and may be optionally substituted by C1-6-alkyl,
as well as the isomers and salts thereof.
Of particular value are those compounds of the general formula I, in which
A is the group xe2x95x90NR7,
W is oxygen,
Z is a bond,
R1 is branched or unbranched C1-12-alkyl or C2-12-alkenyl which is optionally substituted once or many times by halogen, hydroxy, C1-6-alkyloxy, aralkyloxy, C1-6-alkyl and/or NR11R12; or C3-10-cycloalkyl, or C3-10-cycloalkenyl which is optionally substituted once or many times by halogen, hydroxy, C1-6-alkyloxy, aralkyloxy, C1-6-alkyl and/or NR11R12,
X is C1-6-alkyl;
R2 is pyridyl,
R3, R4, R5 and R6 are hydrogen, halogen; or C1-6-alkoxy, C1-6-alkyl, C1-6-carboxyalkyl either unsubstituted or optionally substituted once or many times by halogen,
R7 is hydrogen, C1-6-alkyl or C1-8-cycloalkyl,
R9 is hydrogen or C1-6-alkyl and
R11 and R12 are hydrogen or C1-6-alkyl, or form a ring which may contain oxygen or nitrogen as a further hetero atom and may be optionally substituted by C1-6-alkyl,
as well as the isomers and salts thereof.
The compounds of the general formula I which have proved to be especially valuable are those in which
A is the group xe2x95x90NR7,
W is oxygen,
Z is a bond,
R1 is branched or unbranched C1-12-alkyl which is optionally substituted once or many times by halogen, C1-6-alkyloxy or NR11R12; or C3-10-cycloalkyl which is optionally substituted once or many times by hydroxy, C1-6-alkyloxy, C1-6-alkyl or benzyloxy,
X is C1-6-alkyl;
R2 is pyridyl,
R3, R4, R5 and R6 are hydrogen,
R7 and R9 are hydrogen,
R11 and R12 are hydrogen or C1-6-alkyl or form a morpholinyl, piperidinyl, pyrrolidinoyl or tetrahydrofuranyl ring, which may be optionally substituted by C1-6-alkyl,
as well as the isomers and salts thereof.
The compounds according to the invention prevent phosphorylation, i.e. certain tyrosine kinases can be selectively inhibited, whereby the persistent angiogenesis can be stopped. In this way, for example, the growth and spread of tumours is suppressed.
The compounds of the general formula I according to the invention also contain the possible tautomeric forms and include the E- or Z-isomers, or if a chiral centre is present, also the racemates and enantiomers.
Owing to their inhibitory activity in respect of phosphorylation of the VEGF receptor, the compounds of formula I and their physiologically acceptable salts may be used as medicaments. Owing to their profile of activity, the compounds according to the invention are suitable for treating diseases caused by or accelerated by persistent angiogenesis.
Since the compounds of formula I are identified as inhibitors of KDR and FLT tyrosine kinase, they are especially suitable for treating those diseases that are caused by or accelerated by the persistent angiogenesis, triggered by the VEGF receptor, or by an increase in vascular permeability.
The object of the present invention is also the use of the compounds according to the invention as inhibitors of KDR and FLT tyrosine kinase.
A further object of the present invention is thus the medicaments for treating tumours, and their use.
The compounds according to the invention may be used either on their own or in a formulation as a medicament for treating psoriasis, arthritis, such as rheumatoid arthritis, haemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplantation rejections and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferation diseases, artheriosclerosis and injuries to nerve tissue.
When treating injuries to nerve tissue, the compounds according to the invention can prevent rapid formation of scar tissue at the site of the wounds, i.e. the onset of scar formation is prevented before the axons join together again. Thus, reconstruction of the nerve unions is simplified.
In addition, the compounds according to the invention suppress ascites formation in patients. Similarly, VEGF-induced oedema are suppressed.
Such medicaments, their formulations and uses are likewise objects of the present invention.
The invention further relates to the use of the compounds of the general formula I in the production of a medicament for treating tumours, psoriasis, arthritis, such as rheumatoid arthritis, haemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplantation rejections and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferation diseases, artheriosclerosis and injuries to nerve tissue.
When using the compounds of formula I as medicaments, they are brought into the form of a pharmaceutical preparation, which contains, in addition to the active ingredient for enteral or parenteral application, appropriate pharmaceutical, organic or inorganic inert carriers, for example water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. The pharmaceutical preparations may exist in solid form, for example as tablets, coated tablets, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions. They may additionally contain excipients such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers.
For parenteral application, injection solutions or suspensions are especially suitable, particularly aqueous solutions of the active compounds in polyhydroxy-ethoxylated castor oil.
Surface-active excipients may also be used as carrier systems, for example salts of bile acid or animal or vegetable phospholipids, and also mixtures thereof, as well as liposomes or constituents thereof.
For oral application, tablets, coated tablets or capsules are especially suitable, with talcum and/or hydrocarbon carriers or binders, for example lactose, corn starch or potato starch. Application may also be carried out in liquid form, for example as juice, to which a sweetener and/or a flavouring agent may optionally be added.
Dosaging of the active ingredients may vary according to the mode of administration, the age and the weight of the patient, the nature and severity of the illness to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose may be given as a single dose to be administered once or may be divided into two or more daily doses. The above-described formulations and dosage forms are likewise objects of the present invention.
Preparation of the compounds according to the invention is carried out according to known methods. For example, the compounds of formula I are obtained, whereby
a) in a compound of formula II: 
wherein R3 to R6 are defined as above and A is OR13, whereby R13 is hydrogen or C1-4-alkyl or C1-4-acyl, first of all the amine is alkylated and then COA is converted into an amide, or
b) in a compound of formula III: 
wherein R3 bis R6 are defined as above, and A is halogen or OR13, whereby R13 may be hydrogen, lower alkyl or acyl, COA is converted into an amide, the nitro group is reduced to the amine and is then alkylated,
In all cases, the sequence of steps can be switched.
Amide formation is effected according to methods known in literature.
An amide may be formed from a corresponding ester. The ester is reacted in accordance with J. Org. Chem. 1995, 8414 with aluminium trimethyl and the corresponding amine in solvents such as toluene at temperatures of 0xc2x0 C. to boiling point of the solvent. If the molecule contains two ester groups, both are converted to the same amide.
When using nitriles instead of the ester, amidines are obtained under analogous conditions.
To form the amide, all methods that are known from peptide chemistry may be used. For example, the corresponding acid can be reacted with the amine in aprotic polar solvents, for example dimethylformamide via an activated acid derivative, for example obtainable with hydroxybenzotriazole and a carbodiimide, such as diisopropyl carbodiimide, or also with prepared reagents, for example HATU (Chem. Comm. 1994, 201) or BTU, at tempertures between 0xc2x0 C. and boiling point of the solvent. To form the amide, the method using the mixed acid anhydride, the acid chloride, the imidazolide or the azide may also be employed. For reactions of the acid chloride, the solvent dimethyl acetamide is preferred at temperatures from room temperature to boiling point of the solvent, preferably 80-100xc2x0 C.
If different amide groups are to be introduced into the molecule, the second ester group must be introduced into the molecule for example after producing the first amide group, and is then amidated, or a molecule exists in which one group is present as an ester and the other as an acid, and the two groups are amidated after each other by different methods.
Thioamides may be obtained from the anthranilamides by a reaction with diphosphadithianes according to Bull Soc. Chim. Belg. 87, 229, 1978 or by a reaction with phosphorus pentasulfide in solvents such as pyridine or also without any solvents at all at temperatures of 0xc2x0 C. to 200xc2x0 C.
Reduction of the nitro group is carried out in polar solvents at room temperature or at elevated temperature. Suitable catalysts for reduction are metals such as Raney nickel or noble metal catalysts such as palladium or platinum or also palladium hydroxide, optionally on carriers. Instead of hydrogen, ammonium formate, cyclohexene or hydrazine may also be used, for example, in known manner. Reducing agents such as tin II chloride or titanium (III) chloride may be used in the same way as complex metal hydrides, optionally in the presence of heavy metal salts. Iron may also be used as a reducing agent. In this case, the reaction is carried out in the presence of an acid, such as acetic acid or ammonium chloride, optionally adding a solvent, for example water, methanol, iron/ammonia etc. In the prolonged reaction time in this variant, acylation of the amino group can occur.
If alkylation of an amino group is desired, alkylation may be effected by the usual methodsxe2x80x94for example with alkyl halidesxe2x80x94or by the Mitsonubo variant by a reaction with an alcohol in the presence of for example triphenylphosphine and azodicarboxylic acid ester. The amine may also undergo reductive alkylation with aldehydes or ketones, whereby the reaction is carried out in the presence of a reducing agent, for example sodium cyanoborohydride in a suitable inert solvent, for example ethanol, at temperatures from 0xc2x0 C. to boiling point of the solvent. When starting with a primary amino group, the reaction is effected optionally with two different carbonyl compounds after one another, whereby mixed derivatives are obtained [literature e.g. Verardo et al. Synthesis (1993), 121; Synthesis (1991), 447; Kawaguchi, Synthesis (1985), 701; Micovic et al. Synthesis (1991), 1043].
It may also be advantageous to firstly form the Schiff""s base by reacting the aldehyde with the amine in solvents such as ethanol or methanol, optionally adding excipients such as glacial acetic acid, and only then to add reducing agents, e.g. sodium cyanoborohydride.
Ether cleavages are carried out by conventional methods known from literature. Here, even if several groups are present in the molecule, selective cleavage can be achieved. The ether is treated for example with boron tribromide in solvents such as dichloromethane at temperatures between xe2x88x9210xc2x0 C. and boiling point of the solvent, preferably at xe2x88x9278xc2x0 C. However, it is also possible to cleave the ether by means of sodium thiomethylate in solvents such as dimethylformamide. The temperature may be between room temperature and boiling point of the solvent, preferably 150xc2x0 C. In the case of benzyl ethers, cleavage is also effected with strong acids, for example trifluoroacetic acid, at temperatures from room temperature to boiling point, preferably at 70xc2x0 C.
The isomeric mixtures can be separated by conventional methods, for example crystallisation, any form of chromatography or by salt formation, into the enantiomers or E/Z-isomers.
Production of the salts takes place in conventional manner, by mixing a solution of the compound of formula I with the equivalent amount or with an excess of a base or acid, which is optionally in solution, and separating the precipitate or by working up the solution in conventional manner.
The following examples illustrate the preparation of the compounds according to the invention without limiting the scope of the compounds being claimed to these examples.